Joint Effects of Air Pollution and Cerebral Hypoperfusion: Age and Sex Influence Emerging evidence suggests a strong association between traffic-related air pollution (TRAP) and cognitive aging. Clinical and experimental studies demonstrate white matter toxicity and hippocampal neuronal atrophy in the setting of particulate matter (PM) exposure. Little is known, however, about the underlying pathophysiology and selective vulnerabilities. Evidence supports a critical role for cerebral vascular dysfunction in the onset and progression of Alzheimer's disease (AD), with cortical hypoperfusion implicated in the pathogenesis of neuronal dysfunction and cognitive deficits. Studies have demonstrated increased memory impairment, hippocampal neuronal loss, and altered A? metabolism in APPSwInd and APP overexpressing mice exposed to chronic cerebral hypoperfusion (CCH). Individuals with AD or cognitive impairment may demonstrate increased susceptibility to deleterious effects of TRAP exposure through vascular mechanisms. This program leverages experimental models focused exclusively on the cerebrovascular contributions to AD/ cognitive decline. We hypothesize that nanoparticulate matter (nPM) exposure and CCH exhibit synergistic effects on neurodegenerative pathways from the entorhinal cortex and hippocampus including the perforant pathway and diffuse white matter tracts. Age and sex variances are evident in AD prevalence, with older women most affected. These factors also impact cerebrovascular reserve, ischemic injury response, and BBB permeability. The proposed project seeks to determine age and sex influences on nPM and CCH exposure alone, and in combination, through the following specific aims: 1) Examine age dependence for the individual/ joint effects of nPM exposure and CCH on white matter toxicity, hippocampal / entorhinal cortex neuronal injury, and neurocognition, 2) Examine sex differences in the independent/ joint effects of nPM and CCH on the above outcomes and, 3) Examine mechanistic pathways by which nPM promotes neurodegenerative processes in the setting of CCH. The nPM exposure model has been used in our group's prior studies. Near roadside urban nPM is collected by means of innovative particle samplers developed by the USC Aerosol group (Sioutas). Whole body exposures are administered. The CCH model has been refined and leveraged to examine inflammatory mediators and BBB. A factorial design will assess independent and combined effects of nPM and CCH on white matter toxicity, hippocampal/ entorhinal cortex injury, and neurocognition. When administered together, we expect these exposures to exhibit synergy. Consistent with AD pathologies, we expect older female mice to demonstrate greatest vulnerability. We hypothesize that effects are associated with inflammatory upregulation and BBB permeability. Baseline interactions established in wild type mice and data from Project 3 will be leveraged to study mechanism in EFAD-Transgenic and inducible macrophage/ microglial specific TLR4 knockout mice. Expected knowledge will advance our understanding of age and sex impact on neurotoxicity secondary to air pollution and vascular mechanisms of cognitive decline evident in AD.